Project Summary/Abstract Alzheimer?s disease (AD) is characterized by the accumulation of multiple proteins including (APP)/A?, Tau, TDP-43 and alpha-synuclein (?-syn). The mechanisms are not completely understood however alterations in protein aggregate clearance including endosomal sorting complex required for transport (ESCRT) mediated autophagy might be involved. For the previous period of funding, the focus was to investigate the role of autophagy in the mechanisms of propagation and clearance of ? -syn and to develop new immunotherapies for the Dementia with Lewy bodies (DLB). We found that ? -syn interferes with intracellular trafficking and autophagy and that treatment with antibodies reduced propagation and toxicity. We published over 150 manuscripts and 3 of our programs targeting ? -syn have advanced to Phase I clinical trials. For the renewal we will investigate the role of ? -syn as a mediator of the toxicity of A? to selected neuronal populations in AD. Our HYPOTHESIS is that via interactions with Rabs and ESCRTIII proteins, ? -syn aggregates interfere with neuronal endosomal transport of neurotrophic factors (NTFs) leading to selective neuronal damage. Our OBJECTIVES will be to: i) investigate the role of ? -syn as mediator of the selective neuronal loss in AD by interfering with Rabs and ESCRTIII leading to defective transport of NTFs and ii) assess if brain-penetrating nucleotides targeting ? -syn might reverse the endosomal alterations and protect selected networks from degenerating in AD. Our revised AIMS are to: 1) Investigate in neuronal cultures the mechanisms through which ? -syn mediates selective neuronal vulnerability in AD via alterations in Rabs and ESCRTIII; 2) To determine in vivo if conditional ablation of ? -syn in specific neuronal populations in APP mice ameliorates neurodegeneration and functional alterations and 3) To evaluate the neuroprotective effects of brain targeted ? -syn siRNA in APP tg models. These goals are in agreement with the NIA 2012 and 2015 AD Summit Research Recommendations. A better understanding of the mechanisms underlying selective vulnerability in AD is crucial for developing novel therapeutics targeting ? -syn.